Heart Failure Disturbs Gut–Blood Barrier and Increases Plasma Trimethylamine, a Toxic Bacterial Metabolite

Abstract

Trimethylamine (TMA) is a gut bacteria product oxidized by the liver to trimethylamine-N-oxide (TMAO). Clinical evidence suggests that cardiovascular disease is associated with increased plasma TMAO. However, little headway has been made in understanding this relationship on a mechanistic and molecular level. We investigated the mechanisms affecting plasma levels of TMAO in Spontaneously Hypertensive Heart Failure (SHHF) rats. Healthy Wistar Kyoto (WKY) and SHHF rats underwent metabolic, hemodynamic, histopathological and biochemical measurements, including tight junction proteins analysis. Stool, plasma and urine samples were evaluated for TMA and TMAO using ultra performance liquid chromatography-mass spectrometry. SHHF presented disturbances of the gut–blood barrier including reduced intestinal blood flow, decreased thickness of the colonic mucosa and alterations in tight junctions, such as claudin 1 and 3, and zonula occludens-1. This was associated with significantly higher plasma levels of TMA and TMAO and increased gut-to-blood penetration of TMA in SHHF compared to WKY. There was no difference in kidney function or liver oxidation of TMA to TMAO between WKY and SHHF. In conclusion, increased plasma TMAO in heart failure rats results from a perturbed gut–blood barrier and increased gut-to-blood passage of TMAO precursor, i.e., TMA. Increased gut-to-blood penetration of bacterial metabolites may be a marker and a mediator of cardiovascular pathology.

Assessment of trimethylamine N-oxide (TMAO) as a potential biomarker of severe stress in patients vulnerable to posttraumatic stress disorder (PTSD) after acute myocardial infarction

“…A previous experiment with rats suggested that heart failure might be associated with functional and structural alterations in intestinal integrity, leading to increased gut-to-blood penetration of TMA and a subsequent elevation in serum TMAO levels (Drapala et al, 2020 ). In contrast to heart failure, acute coronary syndrome, which includes AMI, is an acute cardiological disease and a severe medical emergency associated with a sudden reduction in blood flow to the heart.…”

Intestinal Barrier Dysfunction Exacerbates Neuroinflammation via the TLR4 Pathway in Mice With Heart Failure

“…However, the change in intestinal barrier function may be underappreciated. Recently, Drapala et al (2020) reported that rats with HF caused by spontaneous hypertension exhibited intestinal barrier dysfunction and increased intestinal permeability, which could drive intestinal microbiota translocation into systemic circulation, further activate the systemic immune response and exacerbate damage to other organs (Chen et al, 2019). In particular, the intestinal flora metabolite lipopolysaccharide (LPS) is closely associated with a variety of CNS diseases (Zhao et al, 2017).…”

The Gut Microbial-Derived Metabolite Trimethylamine N-Oxide and Atrial Fibrillation: Relationships, Mechanisms, and Therapeutic Strategies

“…Surprisingly, at present, more and more studies have found that TMAO is inextricably linked to hypertension, 9 chronic obstructive pulmonary disease, 19 heart failure, 11,17,20 obesity, 21 metabolic dysfunction, 22 atherosclerosis and coronary heart diseases, 9,10,23 which are known as the common risk factors for AF and motivates a renewed interest in examining the relation between TMAO and AF. However, these results have not been confirmed in AF models and prospective clinical studies, and the degree and mechanism of modifying these risk factors on AF by regulating intestinal microbes and their metabolites such as TMAO are still needed to be explored.…”